Phase I trial of dacarbazine with cyclophosphamide, carmustine, etoposide, and autologous stem-cell transplantation in patients with lymphoma and multiple myeloma

Purpose: We investigated the feasibility of escalating doses of dacarbazine (DTIC) in combination with high-dose cyclophosphamide, carmustine, and etoposide (CBV) given with autologous stem-cell transplantation in 33 patients with relapsed or refractory lymphoma or multiple myeloma. Patients and Methods: Eligible patients were treated in this phase I study with cyclophosphamide (7.2 g/m²), carmustine (BCNU) (600 mg/m²), etoposide (2.4 g/m²), and escalating doses of DTIC (3,000 to 6,591 mg/m²) administered either as a 2- (in 23 patients) or a 6- (in 10 patients) hour infusion to determine the maximum-tolerated dose (MTD) of DTIC and the toxicity profile of this combination. Results: The MTD of DTIC infused over 2 hours and given with the CBV regimen was 3,900 mg/m², with the dose- limiting toxicity being hypotension. Seven patients experienced transient acute hypocalcemia in association with the DTIC infusion. Prolonging the DTIC infusion to 6 hours or administration of supplemental calcium did not allow further dose escalation of DTIC to occur. Other nonhematologic toxicities observed with this regimen have been reported with CBV alone. Of 25 patients assessable for tumor response at first evaluation posttransplant, 13 (52%) were in complete remission (CR), four (16%) were in partial remission (PR), five (20%) had stable disease (SD), and three (12%) had progressive disease (PROG). Of 31 patients assessable for relapse-free survival, 22 are alive with 13 in CR, one in PR, two with SD, and six with PROG at a median follow- up duration of 313 days (range, 35 to 749+). Treatment-related mortality occurred in six patients (18%). Conclusion: The feasibility of combining DTIC in high doses with the CBV regimen has been demonstrated. Dose-limiting hypotension is transient and reversible when DTIC is administered at 3,900 mg/m² with CBV. Future trials to evaluate the effect of the addition of DTIC to the CBV regimen on response rate and relapse-free survival are encouraged.